An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity is increasingly being recognized as a critical barrier to overcome stimulus resistance. Combination stimulus therapy is a treatment option that promises to improve cancer treatment by targeting multiple signaling and regulatory pathways maintaining tumor progression. This type of stimulus regimen is predicated on the concept that stimulus resistance to monotherapy is largely attributed to intratumoral heterogeneity. Therefore, it is important to take into account a targeted tumor's intratumoral heterogeneity when developing a combination stimulus regimen for the targeted tumor. Furthermore, as the number of potential FDA approved drugs increases, systematic approaches to identify combination strategies that account for this level of heterogeneity become imperative.